Infertility is the failure of a couple to conceive a pregnancy after regular sexual intercourse over a given period of time, typically one year, but in some cases 2-3 years. On average, 85% of married couples will have a pregnancy in one year, and a study showed that 25% conceived within 1 month, 70% within 6 months, and 85% within 1 year. After fertility reaches its peak at about the age of 24 in both men and women, the time to conception increases two-fold for every five years they get older. Fertility sharply diminishes from about the age of 35.
The causes of infertility can involve one or both partners. When the problem exists within the male partner, it is referred to as male infertility, and within the female partner, it is referred to as female infertility. According to statistics, male or female infertility accounts for 70% of all infertility cases. Approximately 20% of them are caused by a mix of male and female factors, and approximately 10-15% of them by unknown factors.
The global infertility treatment market exceeded one billion dollars in 2006, and the annual growth rate was around 6%, and it is expected to exceed 1.2 billion dollars in 2011. In Korea, the market sharply increased from 9 billion won in 2006 to 12 billion won in 2007, and a remarkable growth is expected in the coming five years.
A fertility drug is also called an ovulatory stimulant, which is represented by human follicle-stimulating hormone. Human follicle-stimulating hormone is a glycoprotein hormone that is produced by the pituitary gland and released into the endocrine system, and consists of non-covalently linked alpha- and beta-subunits that have 92 and 111 amino acids, respectively, and there are two asparagines-linked carbohydrate chains on each subunit (Mol Hum Reprod, 1996; 2(5): 371-382).
Insufficient production or secretion of follicle-stimulating hormone fails to induce ovulation, leading to infertility in women, and also fails to produce an adequate number of sperms, leading to infertility in men. Therefore, follicle-stimulating hormone has been used for the treatment of infertility, and it was isolated and purified from the urine of women at first. Like other protein drugs, 80% or more thereof have been currently replaced with recombinant products because of safety concerns. The recombinant products are represented by ‘Gonal-F’ of Merck-Serono (MSD), ‘Puregon’ of Organon, etc.
It has been known that ovulation disorders and tubal blockage account for 35%, endometriosis accounts for 20%, and unknown factors account for 10% of female infertility. Assisted reproductive technology, including in-vitro fertilization embryo transfer (IVF-ET), gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), and intra-cytoplasmic sperm injection (ICSI), have been used for the treatment of female infertility. These procedures require ovulation induction, which is performed by the use of human follicle-stimulating hormone. This hormone is also used for anovulatory women. The causes of male infertility are largely divided into sperm disorders and anatomical abnormalities, and the low sperm count can be treated with the use of human follicle-stimulating hormone.
In the treatment of female infertility by assisted reproductive technology, FSH is usually given at an initial dose of 150 IU-225 IU up to 450 IU once a day, on day 2 or 3 of the ovulation cycle, for 5 days up to 20 days until follicle development is adequate. In the treatment of anovulation, FSH is usually given at an initial dose of 75-150 IU, and if necessary, at a dose of 37.5 IU or 75 IU up to 225 IU once a day at 7 or 14 day intervals for up to 4 weeks. In the treatment of male infertility, FSH is usually given at a dose of 150 IU up to 300 IU three times a week for up to 18 months.
As compared to urine-derived human follicle-stimulating hormone, recombinant human follicle-stimulating hormone currently used is improved in terms of purification yield and stability of supply, especially in terms of safety. However, it is still disadvantageous in that patients should be given treatment for ten consecutive days during a treatment period, and infertile male patients should be treated for up to 18 months, imposing a high economic burden on the patients. Such infertility treatments should be continued in both men and women until a successful pregnancy is achieved. Therefore, it is important to reduce the treatment frequency in terms of patient's convenience and cost reduction, and there is an urgent need to develop long-acting products, similar to the strategies for the development of other protein drugs.
By this demand, studies on long-acting products have been conducted to develop hyperglycosylated FSH (MerckSerono) and CTP (carboxy terminal peptide)-attached FSH-CTP formulation (Schering-plough), which are currently under clinical trials. Of them, hyperglycosylated FSH was prepared by the substitution of the relevant amino acid residues in order to increase the half-life of native FSH (WO-2005020934), and is currently under phase II clinical trial. However, it has been reported that the resulting increase in half-life is less than 2-fold, being shorter than that of FSH-CTP (corifollitropin alfa), and immunological problems are also generated due to modification of amino acids. FSH-CTP (U.S. Pat. No. 5,585,345) was prepared by linking the N-terminal peptide of FSH beta subunit with the C-terminal peptide of the beta subunit of human chorionic gonadotropin, which is one of the gonadotropic hormones. The CTP unit contains four glycosylation sites at the serine residues to remarkably increase the serum half-life of hCG, compared to FSH (Hum Reprod, 2002; 17(8): 1987-1993). At present, FSH-CTP is under schering-plough's phase III clinical trial, and its efficacy on the assisted reproduction program for female patients was known to be similar to that of FSH. Reportedly, the pregnancy rates of native and long-acting forms were about 38%, and FSH-CTP can be prepared as a once-a-week formulation. As described above, follicle development usually takes 10 days, even though there are differences between patients. Thus, additional treatment of native FSH may be required when an assisted reproduction program is conducted using the once-a-week formulation. Further, the initial dose of FSH-CTP exceeds the total dose of native FSH given for one week, which may increase the risk of side-effects such as ovarian hyper-stimulation syndrome.